Peroxisome Proliferator-Activated Receptor {gamma} and Growth Inhibition by Its Ligands in Uterine Endometrial Carcinoma

doi:10.1158/1078-0432.CCR-05-1833

Human Cancer Biology

Peroxisome Proliferator-Activated Receptor ${gamma}$ and Growth Inhibition by Its Ligands in Uterine Endometrial Carcinoma

Kyoko Ota¹, Kiyoshi Ito¹, Takashi Suzuki², Sumika Saito¹, Mitsutoshi Tamura¹, Shin-ichi Hayashi³, Kunihiro Okamura¹, Hironobu Sasano² and Nobuo Yaegashi¹

Authors' Affiliations: Departments of ¹ Obstetrics and Gynecology, ² Pathology, and ³ Molecular Medical Technology, Tohoku University Graduate School of Medicine, Sendai, Japan

Requests for reprints: Nobuo Yaegashi, Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. Phone: 81-22-717-7254; Fax: 81-22-717-7258; E-mail: yaegashi{at}mail.tains.tohoku.ac.jp.

Purpose: In this study, we evaluated the correlation betweenendometrial carcinoma and peroxisome proliferator-activatedreceptor ${gamma}$ (PPAR ${gamma}$ ) expression and assessed whether PPAR ${gamma}$ ligandsinfluence carcinoma growth.

Experimental Design: We examined the presence and cellular distributionof PPAR ${gamma}$ protein in 42 normal endometria, 32 endometria withhyperplasia, and 103 endometria with endometrial carcinoma byimmunohistochemistry. We then compared PPAR ${gamma}$ mRNA expressionin endometrial carcinoma with that in normal endometria usingreal-time reverse transcription-PCR. We subsequently confirmedexpression of PPAR ${gamma}$ mRNA by real-time reverse transcription-PCRand PPAR ${gamma}$ protein by immunoblotting in endometrial carcinomacell lines (Ishikawa, Sawano, and RL95-2 cells). We furtherexamined the effects of PPAR ${gamma}$ agonist 15-deoxy- ${Delta}$ ^12,14-prostaglandinJ₂ (15d-PGJ₂), a naturally occurring PPAR ${gamma}$ ligand, to these endometrialcarcinoma cell lines. We also examined the status of apoptosisand p21 mRNA expression of these endometrial carcinoma celllines following addition of 15d-PGJ₂.

Results: PPAR ${gamma}$ immunoreactivity was detected in 11 of 23 (48%)of proliferative-phase endometrium, 14 of 19 (74%) of secretory-phaseendometrium, 27 of 32 (84%) of endometrial hyperplasia, and67 of 103 (65%) of carcinoma cases. PPAR ${gamma}$ immunoreactivity wassignificantly lower in endometrial carcinoma than in secretory-phaseendometrium (P = 0.012) and endometrial hyperplasia (P = 0.006).There was a significant positive association between the statusof PPAR ${gamma}$ and p21 expression in endometrial carcinoma (P <0.0001). There was a significant negative association betweenthe body mass index and PPAR ${gamma}$ labeling index of carcinoma tissuein the patients with endometrial carcinoma (P < 0.0001).PPAR ${gamma}$ mRNA was expressed abundantly in normal endometria butnot in endometrial carcinoma. We showed that PPAR ${gamma}$ agonist 15d-PGJ₂inhibited cell proliferation and induced p21 mRNA of endometrialcarcinoma cell lines.

Conclusion: We showed the expression of PPAR ${gamma}$ in human endometrialcarcinoma and the effects of PPAR ${gamma}$ ligand in endometrial carcinomacells. These findings suggest that a PPAR ${gamma}$ ligand, 15d-PGJ₂,has antiproliferative activity against endometrial carcinoma.

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